SUMMARY (Project II) Though significant progress has been made in the in-vivo detection of amyloid and other biomarkers, few advances have occurred in the last few decades in the development of sensitive and effective memory and other cognitive measures to assess the earliest manifestations of AD. There is a need to develop new neuropsychological measures, which correlate with changes in biomarkers as the subject transitions from a cognitively normal (CN) state to PreMCI or early mild cognitive impairment (MCI). In earlier studies our group has found that instruments which exploited the vulnerability of MCI patients to proactive and retroactive semantic interference (pSI and rSI), were more predictive of early MCI and progression to dementia than traditional cognitive measures and are more highly correlated to the severity of medial temporal atrophy on MRI and with brain amyloid load than traditional neuropsychological measures commonly employed in AD research. Other promising assessment approaches have been developed recently, including a non-verbal memory binding paradigm (SVMB), which have been sensitive to detection of early MCI and impairments in asymptomatic carriers of the E280A presenilin-1 AD mutation and our use of novel non-verbal cognitive approaches such as the spatial navigation test (SNT) which may be sensitive to early hippocampal dysfunction. This has important implications for improving early diagnosis of AD, detecting longitudinal change and improving selection criteria in clinical trials. In Project II, we will enroll 300 subjects 70+ years old from Core B, (150 Hispanic subjects who speak Spanish as their primary language and 150 non-Hispanic subjects (NH) who speak English as their primary language). One-third of the total 300 enrolled participants will be diagnosed with early amnestic mild cognitive impairment (eMCI), one-third will be diagnosed with PreMCI and one-third will be diagnosed as cognitively normal (CN). The goals of the proposed study are to: 1) further validate novel measures of learning, spatial mapping, and semantic interference (LASSI-LE, SVMB, SNT), in the assessment of a culturally diverse sample of older adults with early amnestic MCI; 2) to evaluate the validity and utility of these new instruments in accurately identifying PreMCI states, which our research shows is an at-risk group for progressive cognitive and functional decline; 3) compare the utility of these new instruments to traditional cognitive and functional measures in distinguishing between diagnostic groups; 4) determine the association of the LASSI-LE, SVMB test and the SNT (relative to traditional neuropsychological measures) to baseline amyloid load and atrophy in AD signature regions obtained from structural MRI; and 5) determine the comparative predictive utility of the LASSI-LE, SVMB test and SNT, relative to traditional cognitive measures, in longitudinal assessments of cognition, function and volumetric change on MRI in selected brain regions.